Merck Plans to Initiate Phase 2 C-CREST Program to Evaluate Merck’s Triple Combination of Grazoprevir/Elbasvir with MK-3682 (formerly IDX21437), a Novel Nucleotide Inhibitor, in Q1 2015
Sunday, November 9, 2014 6:53 pm EST
BOSTON--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the presentation of interim data from the C-SWIFT study exploring the potential of a candidate triple-therapy regimen consisting of the fixed-dose combination of grazoprevir/elbasvir (MK-5172/MK-8742, MK-5172A), the company’s investigational NS3/4A protease inhibitor and NS5A inhibitor, in combination with sofosbuvir, a nucleotide (NS5B) inhibitor for the treatment of chronic hepatitis C virus (HCV) infection. Preliminary findings in treatment-naïve HCV genotype 1- (GT1) infected non-cirrhotic patients, following six and four weeks of treatment, and patients with cirrhotic disease, following eight and six weeks of treatment, will be presented by Dr. Eric Lawitz, vice president, scientific and research development, The Texas Liver Institute, San Antonio, TX and C-SWIFT lead investigator. This poster presentation is part of a late-breaking abstract session at the 65th American Association for the Study of Liver Diseases (AASLD) Annual Meeting, also known as The Liver Meeting®.
“These interim data provide a compelling proof-of-concept for the potential of an eight- or six-week triple therapy course in treatment-naive patients with genotype 1 disease, including cirrhotic patients,” said Dr. Lawitz. “These findings will inform the design of larger studies aimed at understanding the potential of short-duration triple therapy across multiple patient types.”
To date, the investigational triple therapy has shown response rates (sustained virologic response1 [SVR] at 4/8 weeks following therapy) ranging from 80 percent to 94.7 percent in cirrhotic and non-cirrhotic patients following six and eight weeks of treatment in this study, as shown in table 1. The four-week regimen resulted in sub-optimal efficacy.
All 28 patients not achieving SVR4/8 relapsed following the end of therapy. Of these patients, 25 (89%) were genotype 1a (GT1a) and three (11%) were genotype 1b (GT1b) [82% of enrolled subjects were infected with HCV GT1a at baseline]. Sequence analysis of virologic failures is so far available for 23 patients. Wild type virus was determined to be the cause in 12 of the relapsed patients. In the other relapsed patients, 10 had elbasvir-resistant viral variants and one had a variant resistant to both grazoprevir and elbasvir.
In this study, the co-administration of grazoprevir/elbasvir and sofosbuvir was generally well-tolerated. The most common adverse events associated with the triple regimen were: headache (4%), fatigue (2%) and nausea (2%). One patient withdrew from the study for reasons unrelated to treatment.
“Our goal is to establish a simple, effective, well-tolerated regimen that is applicable across the diverse population of patients with HCV,” said Dr. Eliav Barr, vice president, infectious diseases, Merck Research Laboratories. “The preliminary data provide us with the confidence to initiate our C-CREST study to evaluate a triple combination comprising Merck’s investigational candidates from three major therapeutic classes of HCV medicines.”
The C-SWIFT study enrolled a total of 102 treatment-naïve patients with HCV genotype 1 (GT1a and GT1b) infection at The Texas Liver Institute, San Antonio, TX. Treatment-naïve, non-cirrhotic patients were randomized to receive the fixed-dose combination of grazoprevir/ elbasvir (one pill containing 100 mg, 50 mg respectively) plus the nucleotide inhibitor sofosbuvir (400 mg) once daily for eight, six or four weeks. Similarly, treatment-naïve, cirrhotic patients were randomized to receive the investigational combination for either eight or six weeks. The primary endpoint of the study is the percentage of patients achieving sustained virologic response 12 weeks after the completion of therapy (SVR12). An additional analysis of patients with genotype 3 (GT3) HCV enrolled in the C-SWIFT study will be presented at a future scientific congress.
Based upon the interim findings from C-SWIFT and data from the Phase 1 clinical trial for MK-3682, also presented at The Liver Meeting®, Merck plans to initiate Phase 2 clinical trials evaluating the efficacy and safety of two short-duration triple therapy regimens: MK-3682 in combination with grazoprevir/elbasvir; and MK-3682 in combination with grazoprevir and Merck’s investigational early-stage NS5A inhibitor MK-8408, in non-cirrhotic HCV patients. Part A of the Phase 2 studies is planned to evaluate eight weeks of therapy among non-cirrhotic HCV-infected patients, and Part B studies may evaluate shorter courses of treatment based on findings from Part A.
MK-3682 (formerly IDX21437) Data Presentation at AASLD Annual Meeting
MK-3682 is an investigational oral prodrug HCV nucleotide analogue NS5B polymerase inhibitor. Phase 1/2a clinical trial results for MK-3682 are scheduled to be presented in a poster session (Abstract #1974) at The Liver Meeting®. HCV infected subjects (24 GT1 and 20 GT2/3) were randomized to receive placebo or 50, 150 or 300 mg of MK-3682 daily for seven days. Following initial pharmacokinetic and pharmacodynamic analysis, enrollment into the 50 mg and 150 mg treatment groups was discontinued due to a small reduction in viral load. In the 300 mg arms, the mean maximum viral load reductions from baseline for 7-day dosing were 4.6 and 4.1 log10 IU/mL in GT 2 (n=3) and GT 3 subjects (n=7), respectively. In GT1a (n=3) and GT1b subjects (n=5), the mean maximum viral load reductions from baseline for 7-day dosing were 4.8 and 3.9 log10 IU/mL respectively.
To date, no discontinuations due to an adverse event and no drug-related serious adverse events have been reported. Most adverse events were mild or moderate in intensity, with no apparent dose effect. There were no clinically significant abnormalities reported in routine blood and urine biomarker panels and physical examinations. Initial results from this study were previously announced by Idenix Pharmaceuticals in April 2014.
Grazoprevir/elbasvir (MK-5172/MK-8742, MK-5172A) is an investigational, oral, once-daily, fixed-dose combination chronic HCV treatment, consisting of grazoprevir, an investigational oral, once-daily HCV NS3/4A protease inhibitor, and elbasvir, an investigational oral, once-daily HCV NS5A replication complex inhibitor. In October 2013, Merck announced that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to grazoprevir/elbasvir for treatment of chronic HCV infection. Breakthrough therapy designation is intended to expedite the development and review of a candidate that is planned for use, alone or in combination, to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.
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1 Defined as HCV RNA below the limit of quantification or below the limit of detection at the last visit on record – 4, 8, or 12 weeks after the completion of therapy.
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